Structural insights into the activation of human calcium-sensing receptor.

ABSTRACT: Human calcium-sensing receptor (CaSR) is a G-protein-coupled receptor that maintains Ca²⁺ homeostasis in serum. Here, we present the cryo-electron microscopy structures of the CaSR in the inactive and agonist+PAM bound states. Complemented with previously reported structures of CaSR, we show that in addition to the full inactive and active states, there are multiple intermediate states during the activation of CaSR. We used a negative allosteric nanobody to stabilize the CaSR in the fully inactive state and found a new binding site for Ca²⁺ ion that acts as a composite agonist with L-amino acid to stabilize the closure of active Venus flytraps. Our data show that agonist binding leads to compaction of the dimer, proximity of the cysteine-rich domains, large-scale tran

SUBMITTER: Chen X 

PROVIDER: S-EPMC8476121 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature